CXCR3

CXCR receptors (C-X-C Motif Chemokine Receptors) are a family of chemokine receptors that belong to the group of G-protein-coupled receptors (GPCRs). Chemokine receptors are 7-transmembrane G-protein-coupled receptors that are activated by the binding of one or more chemokines.

CXCR receptors play an essential role in the immune system by influencing the migration of immune cells to sites of inflammation or to tissues. Chemokines are signaling molecules produced by various cells. They form a family of chemoattractive molecules, of which more than 50 have been identified to date. Chemokines are categorized into four main groups according to the number and spacing of conserved cysteines: CXC, CC, CX3C and C. They bind to their specific receptors (e.g. CXCR) and thus initiate a signaling cascade that controls the behavior of immune cells, including their movement, activation and differentiation. In individual cases, this can also influence tumor growth.

CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11 (Koper OM et al. 2018). The reeptorr protein is encoded by a gene of the same name(CXCR3 gene) located on chromosome Xq13.1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One of the isoforms (CXCR3-B) shows a high affinity for binding to the chemokine CXCL4/PF4.

CXCL11 binds CXCR3 with a higher affinity than the other ligands, which leads to receptor internalization. CXCL10 not only attracts CXCR3+ CD4+ and CD8+ effector T cells to sites of inflammation, but also controls their polarization into highly effective effector T cells (Karin N 2020). CXCL11 is also able to control the development of T regulatory 1 cells (Tr1). It can be assumed that CXCR3 ligands differentially regulate the biological function of T cells via biased signal transduction. The aforementioned chemokines are particularly involved in the Th1 response and in various diseases, as their expression correlates with tissue infiltration of T cells. Their production is strongly stimulated by interferon gamma (IFN-υ), the classic Th1 cytokine. They all act by binding to the CXC3 receptor (Koper OM et al. 2018).

CXCL10 and possibly CXCL9 differ from other chemokines in their ability to inhibit tumor growth and enhance anti-tumor immunity. Furthermore, a growing number of studies in various human cancers showed a clear association between poor prognosis and low expression of CXCL10 at tumor sites and vice versa (Karin N 2020). This suggests a potential relevance for CXCL9 and CXCL10 in cancer immunotherapy.

1. Karin N (2020) CXCR3 Ligands in Cancer and Autoimmunity, Chemoattraction of Effector T Cells, and Beyond. Front Immunol 11:976
2. Koper OM et al. (2018) CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med 27:849-856.